The effects of adenosine are transduced through adenosine receptors, which are subdivided into four general subtypes; A1, A2A, A2B, and A3, all of which modulate important physiological processes ((G. L. Stiles, K. A. Jacobson, and M. F. Jarvis, Wiley-Liss: New York, (1997); pp 29-37; V. Ralevic; G. Burnstock, G. Pharmacol. Rev. (1998) Vol. 50, 413-492). For example, stimulation of the A1 adenosine receptors shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. Stimulation of cell surface A2A receptors produces dilation of the coronary resistance vessels, which phenomenon is useful for pharmacological stress imaging. A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153). A3 adenosine receptors modulate cell proliferation processes. In particular, compounds that are A3 receptor agonists have utility in the therapeutic and/or prophylactic treatment of cancer, cardiac disease, infertility, kidney disease, and CNS disorders.
Adenosine is an important endogenous purine neuromodulator in the central nervous system. Recently, A2A receptors have been demonstrated to be abundant in the basal ganglia, a region of the brain that is known to be important in motor function. It has been shown that administration of haloperidol or MPTP (N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) produces symptoms similar to Parkinson's disease in test animals, and these symptoms can be reversed by administration of an A2A receptor antagonist (see, for example, “piperazine Derivatives of [1,2,4] Triazolo[1,5-a][1,3,5]triazine as Potent and Selective Adenosine A2A Receptor Antagonists”, by Chi B. Vu et al., Journal of Medicinal Chemistry, 2004).
A2A receptor antagonists also possess neuroprotective properties. A2A antagonists have been shown to block kainate-induced excitotoxicity in the hippocampus, to reduce ischemia-evoked glutamate and aspartate release from the cortex, and to reduce the extent of the ischemia-induced injury in rats and gerbils. Further evidence for A2A receptor mediated neuroprotection arises from studies demonstrating that both cerebral infarct size and neurological deficits following transient ischemia are attenuated in A2A receptor knockout mice.
Stimulation of A2A adenosine receptors produces dilation of the coronary resistance vessels. Although this phenomenon is useful for pharmacological stress imaging, it is not favorable for patients who have elevated endogenous adenosine, because excessive vasodilation potentially leads to coronary steal. The phenomenon of coronary steal can cause tissue damage, because ischemia may be produced in the vascular beds fed by the artery that has lowered blood flow due to the more favorable vasodilation of healthy adjoining arteries. Accordingly, an A2A antagonist will prevent the phenomenon of coronary steal.
It has been shown that adenosine signaling is implicated in drug addiction. All major drugs of abuse (opiates, cocaine, ethanol, and the like) either directly or indirectly modulate dopamine signaling in neurons, in particular those found in the nucleus accumbens, which contains high levels of A2A adenosine receptors. Dependence on addictive substances has been shown to be augmented by the adenosine signaling pathway, and it has been shown that administration of an A2A adenosine receptor antagonist reduces the craving for addictive substances (see, for example, “The Critical Role of Adenosine A2A Receptors and Gi βγ Subunits in Alcoholism and Addiction: From Cell Biology to Behavior”, by Ivan Diamond and Lina Yao, (The Cell Biology of Addiction, 2006, pp 291-316), and “Adaptations in Adenosine Signaling in Drug Dependence: Therapeutic Implications”, by Stephen P. Hack and Macdonald J. Christie, Critical Review in Neurobiology, Vol. 15, 235-274 (2003)).
It has also been demonstrated that adenosine receptors, in particular the A2A adenosine receptor, play a role in down regulation of inflammation in vivo (see U.S. Patent Application Publication No. 2005/0220799) by acting as a termination mechanism that limits the immune response, and consequently protect normal tissues from excess immune damage during pathogenesis of various diseases. Accordingly, inhibition of signaling through the A2A adenosine receptor intensifies and prolongs the immune response in a mammal, and thus, for example, increases the efficacy of a vaccine when an A2A adenosine antagonist is co-administered with a vaccine.
Accordingly, it is desired to provide compounds that are potent A2A antagonists, useful in the treatment of various disease states related to modulation of the A2A receptor, in particular cardiovascular diseases such as tissue damage caused by ischemia, CNS-related diseases such as Parkinson's disease, the treatment of drug addiction, and improved immunization. Preferably, the compounds would be selective for the A2A receptor, thus avoiding side effects caused by interaction with other adenosine receptors.